The present invention relates to novel crystals of depsipeptide derivative (IV) with an antiparasitic activity, and a method for producing the same.
The depsipeptide derivative (IV) represented by the following formula has been known as a compound with an excellent antiparasitic activity to animals and human beings, and WO 93/19053 and WO 97/02256 disclose a method for producing the same. 
The former WO 93/19053 specifically discloses a method for producing amorphous depsipeptide derivative (IV) by way of the following processes (nine processes in total). 
According to the method, however, all the intermediate products produced during the course by way of the compound (B) to the objective compound (IV) have basic morpholino groups within the molecules and therefore, they should be handled with precise caution and they are purified by re-crystallization with much difficulty. Because the resulting objective compound (IV) itself is poor in terms of crystallinity, the compound has a variety of disadvantages in terms of production efficiency and handle-ability such that the compound requires purification by column chromatography and the like. Hence, it cannot be said that the method is suitable for industrial scale.
So as to overcome such problems, thus, the method of the latter WO 97/02256 is proposed. According to the method, a depsipeptide derivative in crystal can be recovered, but the subsequent research works indicate that the crystal is poor in respect of filtration properties during crystallization and of fluidity and specific volume [referring the volume occupied by a unit mass (1 g), which is equal to the reciprocal of the density].
With attention focused on the aforementioned circumstance, the present invention has been attained, and the purpose of the present invention is to provide novel crystals of depsipeptide derivative with excellent filtration properties during crystallization, great fluidity, good specific volume and the like, thereby as a consequence of the improvement in the handle-ability during production, resulting in an enhanced production efficiency and an increased yield of the crystal, and to provide a method for producing such crystals at a high efficiency.
The crystals (I), (II) and (III) of the depsipeptide derivative (IV) according to the present invention capable of overcoming the problems described above, individually have the following physico-chemical properties.
Crystal (I): substantially having the powdery X-ray diffraction characteristic properties described in Table 1 and having an endothermic peak substantially at 155xc2x0 C. by differential thermal analysis.
Crystal (II): substantially exerting the powdery X-ray diffraction characteristic properties described in Table 2 and having an endothermic peak substantially at 182xc2x0 C. by differential thermal analysis.
Crystal (III): substantially exerting the powdery X-ray diffraction characteristic properties described in Table 3 and having an endothermic peak substantially at 194xc2x0 C. by differential thermal analysis.
The methods for producing the crystals (I), (II) and (III) of the depsipeptide derivative (IV) according to the present invention, having overcome the problems, are individually as follows.
Crystal (I)
The following method (1) or (2) may essentially be used.
(1) The depsipeptide derivative (IV) is added to acetone and dissolved therein, followed by further addition of water for crystallization, or
(2) the depsipeptide derivative (IV) is added to tetrahydrofuran, acetonitrile or acetone and dissolved, followed by addition of isopropyl ether for crystallization.
Crystal (II)
The crystal (I) is added to ethanol and dissolved therein, followed by addition of isopropyl ether for crystallization.
Crystal (III)
The crystal (II) is added to ethyl acetate and dissolved therein, followed by further addition of isopropyl ether for crystallization.